Update on ALS

Question 1

Definition of ALS

Answer 1

Age-dependent, progressive, lethal neurodegenerative disease

Question 2

______ individuals in US have ALS

Answer 2

30,000

Question 3

Median age of ALS at onset:

Answer 3

55

Question 4

ALS is selective _____

Answer 4

death of motor neurons

Question 5

ALS is muscle weakness affecting ___, ____, ____.

Answer 5

speech, swallowing, breathing

Question 6

____ progression

Typical survival _____ years from onset

Answer 6

Rapid

2-3 years

Question 7

ALS:
Type of onset: _____
Two types of onset:

Answer 7

Insidious

Extremities, “bulbar”

Question 8

How does ALS progress

Answer 8

spreads to adjacent regions

Question 9

Terminal phase of ALS complications?

Answer 9

respiratory failure, aspiration

Question 10

ALS can present as
LMN: _____ (4 signs)
UMN: ______ (4 signs)

Answer 10

1. Flaccid tone, atrophy, fasciculations, cramps

2. Spastic tone, increased DTRs, babinski, hoffman

Question 11

Name the 5 “more or less” preserved functions in ALS

Answer 11

1. Cognitive - unless frontotemporal dementia or bulbar affect
2. Eye Movement
3. Bladder/bowel
4. Sexual function
5. Sensation

Question 12

ALS definition:

Answer 12

UMN and LMN signs co-existing in a single region. (85-90%)

Question 13

ALS classification:

1. If UMN only?
2. IF LMN only?

Answer 13

1. primary lateral sclerosis (PLS)

2. Progressive Muscular atrophy; progressive bulbar palsy

Question 14

Medical management of ALS:

3

Answer 14

Rilutek
Vitamin E
Antioxidants

Question 15

4 symptoms/complications often treated during ALS

Answer 15

Cramps
Fasciculations
Spasticity
drooling

Question 16

ALS epidemiology:
Bimodal:
Gender:
Race:

Answer 16

65 years 2/100,000

M:F 1.6:1
Blacks ~60% of whites

Question 17

Risk factors for ALS(4)

Answer 17

1. Male gender 1.2-4:1
2. Positive family history
3. “clusters” - western pacific (Guam) ALS/PD
4. Military service

Question 18

“possible” additional risk factors for ALS (7)

Answer 18

1. Neurotoxicant Exposures - Pb, Hg, pesticide, volatile solvents
2. Occupations - electrical workers, farmers
3. Trauma - skeletal trauma, fractures, severe electrical shock with unconsciousness
4. Vigorous physical activity - heavy manual labor, athleticism
5. Lifestyle factors - smoking, ETOH, BMI
6. Diet - highfat intake, glutamate intake, low fiber, antioxidant intake
7. Infecious agents, home pesticide exposure, residential proximity to industry.

Question 19

ALS spares which cranial nerves and nucleus?

Answer 19

3/4/6 and Onuf’s nucleus

Question 20

Name the two cytoplasmic inclusions of ALS

Answer 20

Bunina bodies
Ubiquitin-positive inclusions

(axonal spheroids)

Question 21

7 theories behind pathogenesis of ALS

Answer 21

1. Protein toxicity: FALS, SOD1
2. Oxidative stress - excess production or impaired degradation of reactive oxidized species from metals, molecules, and cellular organelles
3. Mitochondrial abnormalities
4. Glutamate excitotoxicity
5. Neurofilament aggregation, axonal transport
6. RNA processing (TDP-43, FUS)
7. Repeat Expansion (C9orf72) - hexagonal repeat

Question 22

Sporadic cases account for ___% of ALS.

Answer 22

90

Question 23

Median age of onset for familial ALS (FALS)

25% associated with defect in: ____-

Answer 23

35
Autosomal Dominant
Cu, Zn Superoxide dismutase (SOD1) - over 100 mutations defined at SOD1 locus

Question 24

Most common mutation in SOD1 for ALS?

4 others?

Answer 24

A4V is most common SOD1 mutation in North American 
Other genes; 
FUS
TDP-43
ANG
Fig4

Question 25

Mutations in the ____gene on Chromosome 16

Answer 25

FUS/TLS - fused in sarcoma/translated in liposarcoma gene

Question 26

Function of FUS/TLS gene

Answer 26

In ALS. Protein normally binds to RNA, functions in diverse processes, and is normally located in predominantly the nucleus. Mutant forms accumulate in cytoplasm of neurons

Question 27

What appears to be common pathogenic mechanism of ALS on a genetic level?

Answer 27

neuronal cytoplasmic protein aggregation and defective RNA metabolism.

Question 28

Number 1 drug therapy in ALS.

How does it work? 3

Answer 28

Rilutek (riluzole):

1. Inhibitory effect on glutamate release
2. inactivationof voltage-dependent sodium channels
3. ability to interfere with intracellular events that follow transmitter binding at excitator amino acid receptors.